Exendin-4 is a 39 amino acid peptide which is produced by the salivary glands of the Gila monster (Heloderma suspectum) (Eng, J. et al., J. Biol. Chem., 265: 20259-62,1990; Ng, J. et al., J. Biol. Chem., 267:7402-05, 1992). Like GLP-1, exendin-4 is an activator of the GLP-1 receptor. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo (Eng J., Diabetes, 45(Suppl 2):152A (abstract 554), 1996).
The amino acid sequence of exendin-4 is shown as SEQ ID NO: 1:
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2
The amino acid sequence of GLP-1 is shown as SEQ ID NO: 2:
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR
Its actions include stimulation of insulin synthesis and secretion, inhibition of glucagon secretion, and inhibition of food intake. GLP-1 has been shown to reduce hyperglycemia in diabetics.
There is also evidence that GLP-1 and exendin-4 may reduce food intake and promote weight loss (Buse J. B. et al., Lancet, 374:39-47, 2009). This effect would be beneficial not only for diabetics but also for patients suffering from obesity. Such patients with obesity have a higher risk of diabetes, hypertension, hyperlipidemia, cardiovascular disease, and musculoskeletal diseases.
Glucagon is a 29-amino acid peptide which is released into the bloodstream when circulating glucose is low. Glucagon has the amino acid sequence as shown in SEQ ID NO: 3:
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
During hypoglycemia, when blood glucose levels drop below normal, glucagon signals the liver to break down glycogen and release glucose, causing blood glucose levels to rise towards a normal level. Hypoglycemia is a common side effect of insulin therapy in patients with hyperglycemia (elevated blood glucose levels) due to diabetes. Thus, glucagon's most recognized role in glucose regulation is to counteract the action of insulin and maintain blood glucose levels.
Other peptides which bind and activate both the glucagon and the GLP-1 receptor (Hjort et al. Journal of Biological Chemistry, 269, 30121-30124, 1994) and suppress body weight gain and reduce food intake are described in WO 2011/075393, WO 2011/006497, WO 2011/152181, and WO 2011/152182, the contents of which are herein incorporated by reference.
The use of exendin-4 agonists has been proposed for the treatment of diabetes mellitus, reduce of gastric motility, delay of gastric emptying and the prevention of hyperglycemia (U.S. Pat. No. 5,424,286, U.S. Pat. No. 6,858,576, WO98/05351). The use of exendin-4 agonists for reducing food intake is described in WO98/30231, the contents of which are herein incorporated by reference.
Exendin-4 analogues have been described in WO99/43708, WO9/035540, the contents of which are herein incorporated by reference.